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The Rockefeller University Press J. Cell Biol. Vol. 209 No. 2 199210

www.jcb.org/cgi/doi/10.1083/jcb.201410017 JCB 199

JCB: Review

Correspondence to Rizaldy P. Scott: [email protected] used in this paper: ESL, endothelial surface layer; FP, foot pro-cess; GBM, glomerular basement membrane; GEC, glomerular endothelial cell;GFB, glomerular ltration barrier; MC, mesangial cell; PEC, parietal epithelialcell; SD, slit diaphragm.

The mammalian kidney orchestrates the excretion of metabolic

wastes found in blood, a function intimately related to its essen-tial roles in general uid homeostasis and osmoregulation. Itis also important in the control of blood pressure, synthesis ofvitamin D, bone mineralization, and the promotion of erythrocytedevelopment. Despite its modest size (each is approximately thesize of a human st), a mammalian kidney is highly vascularized.A pair of kidneys receives and lters a remarkable volume ofblood, estimated to be the equivalent of roughly 20% of totalcardiac output (Stein and Fadem, 1978; Munger et al., 2011).In humans, blood ltration by the kidneys generates on average1 liter of urine per day. Urine is produced and concentrated alongthe length of nephrons, the basic unit of kidneys (Fig. 1 A). Anadult human kidney is known to contain an average of 1 millionand up to as many as 2.5 million nephrons (Puelles et al., 2011).

A nephron is functionally subdivided into a ltration unitcalled the renal corpuscle or glomerulus and a segmented tubularresorption compartment (Fig. 1 B). The glomerulus is an assembly

of four different cells: the glomerular endothelial cells (GECs),podocytes, mesangial cells (MCs), and parietal epithelial cells(PECs; Figs. 1 C and 2). The word glomerulus is a reference toits intricately tortuous inner capillary tuft formed by GECs,after the Latin word glomus for a ball of yarn (Fig. 2 C). Podo-cytes are specialized perivascular cells aptly named for theirelaborate projections, known as foot processes (FPs) or pedi-cels, that are intimately wrapped around the exterior of glomer-ular capillaries (Fig. 2, A and B). GECs and podocytes share a

common ECM known as the glomerular basement membrane(GBM). The GECs, the podocytes, and the GBM in betweenconstitute the three distinctive layers of the glomerular ltrationbarrier (GFB; Fig. 2 E), an elegant sieve that selectively ltersblood components, generating a dilute primary urinary ltrate.The mesangium, a stalk-like aggregate of MCs and their ECMcalled the mesangial matrix, provides the structural reinforce-ment for the glomerular vasculature. The PECs forms a water-tight cuplike enclosure called the Bowmans capsule. Primaryurinary ltrate collects within the Bowmans capsule and emp-ties through a connected series of epithelial tubules startingfrom the proximal tubules, the loop of Henle, the distal tubules,and a nal collecting duct. The renal tubules of the nephronsand the collecting ducts express various ion and water channels,as well as transporters that help concentrate and adjust the com-position of the urinary ltrate by resorption and secretion. Thislast step is vital for uid conservation, maintenance of electro-lyte balance, and resorption of glucose.

Selective permeability in renal ltration

Water and small solutes (e.g., urea, glucose, amino acids, min-eral ions) in blood plasma freely traverse the GFB while circu-lating cells such as erythrocytes and high-molecular-weightplasma components such as albumin are selectively retained inblood. Intriguingly, the glomerular permeability of proteins,particularly negatively charged proteins such as albumin, is wellexceeded by those of neutral dextrans of comparable or evenlarger sizes (Chang et al., 1975). Additionally, the GFB stronglyrestricts passage of anionic macromolecules (Thomson andBlantz, 2010). Size and charge selectivity thus makes the GFBa formidable barrier for the bulk of plasma proteins and results

The function of the kidney, ltering blood and concentrat-ing metabolic waste into urine, takes place in an intricateand functionally elegant structure called the renal glomer-ulus. Normal glomerular function retains circulating cellsand valuable macromolecular components of plasma inblood, resulting in urine with just trace amounts of pro-teins. Endothelial cells of glomerular capillaries, the podo-cytes wrapped around them, and the fused extracellularmatrix these cells form altogether comprise the glomerularltration barrier, a dynamic and highly selective lter thatsieves on the basis of molecular size and electrical charge.Current understanding of the structural organization andthe cellular and molecular basis of renal ltration drawsfrom studies of human glomerular diseases and animalmodels of glomerular dysfunction.

Beyond the cell

The cell biology of renal ltrationRizaldy P. Scott and Susan E. Quaggin

Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

2015 Scott and Quaggin This article is distributed under the terms of an AttributionNoncommercialShare AlikeNo Mirror Sites license for the rst six months after the pub-lication date (see http://www.rupress.org/terms). After six months it is available undera Creative Commons License (AttributionNoncommercialShare Alike 3.0 Unported license,as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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afferent and efferent arterioles, the glomerular capillaries areheavily perforated with transcellular pores and are not surroundedby smooth muscles. These glomerular capillary pores, known asfenestrae (the plural of fenestra, which means window in Latin),are 60100 nm wide and comprise 20% of the endothelialsurface, making glomerular capillaries efcient portals for therapid passage of high volumes of uid characteristic of renalltration (Fig. 2 D; Levick and Smaje, 1987).

The idea that the glomerular capillary is a bona de lteringcompartment was previously contentious due to the size of its fe-nestrae, which are seemingly wide enough to accommodate albu-min with a molecular dimension of 8 8 3 nm (Sugio et al.,1999). Nevertheless, biophysical studies demonstrate that fenes-trated and nonfenestrated capillaries have comparable permeabil-ities to macromolecules (Sarin, 2010). Recent studies indicatethat the glomerular endothelium plays an active role in renal l-tration on the basis of its negatively charged surface. The lumenof the glomerular capillaries and the fenestral surfaces are linedwith a brous lattice of negatively charged glycoproteins calledthe glycocalyx (Fig. 2 E; Rostgaard and Qvortrup, 2002; Curryand Adamson, 2012). Additionally, plasma components are ad-sorbed within the glycocalyx, forming a broader coat >200 nmthick called the endothelial surface layer (ESL; Hjalmarsson et al.,2004). The lamentous structure and strongly negative chargeof the ESL thus effectively make fenestrae narrower and morerestrictive. Enzymatic destruction of different ESL componentsresulted in elevated albumin excretion accompanied by diminishedESL depth and loss of anionic sites on the endothelial surface(Gelberg et al., 1996; Jeansson and Haraldsson, 2003; Jeanssonand Haraldsson, 2006; Meuwese et al., 2010; Dane et al., 2013).Similar loss of ESL charge density and increased passage of

in a urinary product that is virtually protein-free. While the roleof tubular reuptake of proteins leaked into urine is well recog-nized, recent intravital imaging studies with uorescent albu-min conjugates validate the predominant role of the GFB inensuring minimal loss of albumin in urine (Peti-Peterdi andSipos, 2010).

The diagnostic hallmark of a compromised GFB is theincidence of protein in urine, a condition called proteinuria, ormore specically albuminuria if measured in terms of urinaryalbumin content. Proteinuria manifests in a host of ailmentsranging from congenital nephropathy, hypertension, and diabe-tes to chronic kidney diseases. Over the last two decades, multi-disciplinary studies combining genetics, cell biology, physiology,and signal transduction analysis including extensive studies onproteinuric disease models have provided us with valuable in-sights regarding the physiological importance of each of thethree distinctive layers of the GFB and the intricacies of howthey may function as an integral unit. In this review, we summa-rize our current understanding of the cell and molecular basisof renal ltration, highlighting the development, organization,and properties of each compartment of the GFB, and how theycontribute to selective permeability.

Fenestrated capillaries as primary

portals of renal ltration

The glomerular vasculature consists of afferent and efferentarterioles and the glomerular capillary tuft (Fig. 1 C). Bloodenters and exits the glomerulus via the afferent and efferentarterioles, respectively. Inside the glomerulus, the afferent arterioleimmediately branches into the elaborate glomerular capillarytuft, a specialized region where blood lters through. Unlike the

Figure 1. Anatomical overview of renal ltra-tion. (A) Diagrammatic representation of neph-ron distribution in the kidney. Glomeruli, theltration compartments of nephrons, are foundwithin the kidney cortex. (B) Segmental struc-ture of nephrons. The vascularized glomerulusis found at the proximal end and is connectedthrough a series of renal tubules where urinaryltrate composition is rened through resorptionand secretion. (C) Cellular organization of theglomeruli. GEC, glomerular endothelial cell;AA, afferent arteriole; EA, efferent arteriole;Pod, podocyte; MC, mesangial cell; PEC, pari-etal epithelial cell; PT, proximal tubule; DT, dis-tal tubule; LOH, loop of Henle; CD, collectingduct; BS, Bowmans space.


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201The cell biology of renal ltration Scott and Quaggin

however, causes a latent and progressive hypertrophy of GECswith a concomitant disappearance of fenestrae, a phenomenoncalled endotheliosis (Eremina et al., 2003, 2006). This break-

down of the glomerular endothelium is seen when Vegfa abla-tion is induced in adult mouse podocytes or when its receptor isabsent in GECs, which indicates that VEGFA acts in a paracrinemanner via VEGFR2 (Eremina et al., 2008; Sison et al., 2010).These corroborate earlier ndings showing that inhibition ofVEGFA function causes rapid onset of endotheliosis and pro-teinuria (Sugimoto et al., 2003). Additionally, compound loss ofthe phospholipid-binding ATPases EHD3 and EHD4, which areexpressed exclusively by GECs, strikingly resembles Vegfa hap-loinsufciency and VEGFR2 deciency (George et al., 2011).Their importance in vesicle trafcking suggests that EHD3 andEHD4 likely regulate the recycling of VEGFR2 based on the al-tered cell surface distribution of VEGFR2 in their absence.

Interestingly, podocyte-specic overexpression of VEGFA 164,the predominant VEGFA isoform in the kidney, causes globalcollapse of the glomerular tuft, rapid depletion of GECs, andmassive proteinuria (Eremina et al., 2003). Inducible overex-pression of moderate levels of VEGFA 164 in postnatal and adultpodocytes, however, causes a reversible disruption of glomeru-lar structure and function (Veron et al., 2010a,b). As diabetic pa-tients are known to have elevated levels of circulating VEGFA,these overexpression studies suggest that excessive VEGFA sig-naling could contribute to the progression of diabetic nephropa-thy (Chiarelli et al., 2000; Hovind et al., 2000). These ndings

albumin across the GFB was observed when adsorbed ESLcomponents are eluted by salt perfusion (Fridn et al., 2011).

The role of the ESL in glomerular ltration has also been

examined in proteinuric disease models. Renal perfusion ofadriamycin, a drug used to induce proteinuria in mice, disruptedsynthesis of glomerular proteoglycans and dramatically shriv-eled the glomerular ESL, impairing the size selectivity andcharge density of the GFB (Jeansson et al., 2009). In rats,ageing-related proteinuria correlated with the loss of glomerularESL (Salmon et al., 2012). In both animal models and in humanpatients, diabetes-induced proteinuria has also been stronglycorrelated with damage to the ESL (Salmon and Satchell, 2012).It has been proposed that the ESL could serve as a mechanosen-sor of uid ow, an argument consistent with the loss of vasodi-lation upon removal of the ESL (Curry and Adamson, 2012; Fuand Tarbell, 2013). Altogether these ndings align with the no-tion that the ESL is an essential feature of the glomerular endo-thelium and a crucial determinant of glomerular permeability.

The establishment of a functional GFB is contingent onthe proper development of the glomerular endothelium. Nascentpodocytes secrete VEGFA, a potent chemoattractant and tro-phic factor for migratory angioblasts that become that glomeru-lar endothelium. VEGFA binds the receptors VEGFR1 (Flt1),VEGFR2 (Flk1/Kdr), and neuropilin-1, which are expressed bythese angioblasts (Robert et al., 2000). Homozygous ablation ofVegfa from podocytes results in arrest of glomerular develop-ment and failure to form a GFB. Haploinsufciency for Vegfa ,

Figure 2. An ultrastructural overview ofpodocytes and the glomerular endothelium. (A) Scanning electron micrograph of an ex-posed glomerulus. In this image, the Bowmanscapsule is broken, permitting a striking view ofpodocytes (Pod) completely wrapped aroundthe glomerular capillaries. (B) Higher magni-cation of a podocyte within the glomerulusrevealing the interdigitated FPs. (C) A resincast of the glomerular capillary tuft with thecells corroded to reveal its highly convolutedshape. Image courtesy of F. Hossler (East Ten-nessee State University, Johnson City, TN).(D) Scanning electron micrograph of an ex-posed glomerular capillary and its numerousperforations (fenestrae). (E) Simplied diagramof the GFB. The GEC and its fenestrae arelined by a lamentous glycocalyx enriched innegatively charged proteoglycans. The glyco-calyx and adsorbed plasma components formthe thicker ESL. The GBM is a stratied ECMin between podocytes and GECs. Podocytesform the nal layer of the GFB. The interdigitat-ing FPs of podocytes are linked by porous SDswhere primary urinary ltrate passes through.Bars: (A) 20 m; (B and D) 1 m; (C) 50 m.


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GBM (Candiello et al., 2010), it comes as no surprise thatAlport GBMs are grossly perturbed in composition and aremorphologically distorted. The importance of the collagen IVcomplex in the GBM is further highlighted by Goodpasturesdisease, an autoimmune disorder whereby self-reactive antibod-ies target the 3 subunit of collagen IV, resulting in glomerulo-nephritis (Cui and Zhao, 2011).

Pierson syndrome is an autosomal recessive disorder pre-senting with congenital proteinuria and neuromuscular malde-velopment. Mutations linked to Pierson syndrome map to thegene LAMB2 , which encodes the laminin 2, impairing the as-sembly of the laminin complex LM-521 (a heterotrimer formedamong laminin- 5, - 2, and - 1 subunits; Zenker et al., 2004;Matejas et al., 2010). Mice lacking Lamb2 also show the abnor-mal renal and neuromuscular phenotype of Pierson syndrome,and reveal a distinctive splitting of the GBM (Noakes et al.,1995). In mice, loss of Lama5 in podocytes or the expression ofa hypomorphic allele of Lama5 (causing attenuated expressionof laminin- 5) results in progressive proteinuria and ultra-structural deformation of the GBM (Kikkawa and Miner, 2006;

Shannon et al., 2006; Goldberg et al., 2010). Loss of LM-521 inPierson syndrome causes o ther laminin complexes (LM-111,-211, -332, and -511) to become more prevalent, although thisapparent compensation is insufcient to restore normal GBMstructure and GFB function.

Scanning electron microscopy reveals that the GBM isnot amorphous, but is rather a highly organized labyrinth ofinterconnected polygonal brils of varying thickness rangingfrom 4 to 10 nm (Kubosawa and Kondo, 1985; Hironaka et al.,1993). The brils are most densely packed within the core andhave heterogeneous pores averaging 10 nm in diameter. In aproteinuric nephritis disease model in rodents, it was observedthat the GBM bril network was more loosely packed and had

enlarged pores as big as 40 nm (Hironaka et al., 1996). Imag-ing analysis combining stochastic optical reconstruction mi-croscopy (STORM) and correlative electron microscopy hasrevealed nanometer-resolution details of the highly stratiedorganization of the GBM, delineating the location and orienta-tion of epitopes of major GBM components relative to the ad-hesion receptor integrin- 1 expressed by GECs and podocytes(Fig. 3 A; Suleiman et al., 2013). Collagen IV and nidogen-1both map within the central region of the GBM. In contrast,laminin- 5, agrin, and integrin- 1 bimodally align within twodistinct layers. Interestingly, the 3 4 5 and 1 1 2 (IV)collagen networks are particularly concentrated at the core,closer to the endothelial side, a distribution that is unexpect-edly too distant from the extracellular domains of integrin- 1at the surface of podocytes. This indicates that the physiologi-cally important ligands of podocyte integrin- 1 are the agrinand laminin complexes. Remarkably, this imaging analysis cor-relates well with established domaindomain interactions ofthese GBM components.

Application of correlative STORM imaging to kidneys ofAlport mice ( Col4a3 mutant mice) demonstrates the dramaticredistribution of agrin and 1 1 2 (IV) collagen into a diffusepattern throughout the width of the GBM. A likely implicationof this is that podocytes might be inappropriately exposed to

further indicate that a delicately balanced dosage of VEGFA isnecessary to coordinate the development and maintenance ofthe glomerular vasculature and the GFB.

Signaling via secreted glycoproteins called angiopoietinsintersects with the VEGFA-dependent pathway to balance sta-bilization and remodeling of renal and systemic vasculature(Augustin et al., 2009). The angiopoietin Angpt1 is producedby podocytes and MCs, whereas its cognate receptor Tie2 isexpressed by GECs (Kolatsi-Joannou et al., 2001; Satchell et al.,2002). Inducible knockout of Angpt1 at mid-gestation (frommouse embryonic day 10.5) results in simplied and enlargedglomerular capillary tufts, and the delamination of GECs(Jeansson et al., 2011). Late gestation (embryonic day 16.5) de-letion of Angpt1 does not cause overt glomerular maldevelop-ment but increased susceptibility to diabetic nephropathy. Onefactor that could contribute to impairment of the GFB is the lossof glomerular endothelial glycocalyx, which is caused by dia-betic nephropathy and likely exacerbated by Angpt1 deciency.In systemic vasculature, Angpt1 promotes barrier property andreduced permeability to albumin by stimulating the synthesis

of glycocalyx and thickening of the ESL (Satchell et al., 2004;Salmon et al., 2009). Altogether, these studies underscore theimportance of GECs and the ESL in renal ltration.

The GBM: A highly ordered ECM

and ltration bed

The GBM derives from the fusion of the respective basementmembranes of both podocytes and GECs (Abrahamson, 2012;Miner, 2012). Ultrastructure imaging by electron microscopyreveals a brous and stratied lattice with heterogeneous pores.Proteomic analysis identied 144 distinct proteins in puriedhuman glomerular ECM including the GBM (Byron et al.,2014; Lennon et al., 2014), with the most abundant being colla-

gens (types I, IV, VI, and XVIIII subunits), laminins ( 5, 2,and 1), nidogen-1, heparan sulfate proteoglycans (HSPGs,agrin, and perlecan), and tubulointerstitial nephritis antigen-like(TINAGL1) protein. The GBM is an integral component of theGFB acting as an intermediary sieving matrix. The GBM mayalso function as a sink for pro-angiogenic ligands and secretedfactors that mediate cellular communication between podocytesand GECs. Lastly, the GBM cements podocytes and GEC inplace by cellECM adhesive interactions, thus effectively stabi-lizing the GFB. Among the abundant components of the GBM,type IV collagens and laminins are the most indispensable.

Alport syndrome is a hereditary disorder that targets theGBM, causing mild proteinuria during adolescence and pro-gressing to end-stage renal failure. This ailment is linked tomutations in the genes COL4A3 , COL4A4 , and COL4A5 , whichencode the type IV collagen subunits 3, 4, and 5, respec-tively. Maturation of the GBM involves the substitution of the

1 1 2 (IV) collagen with the 3 4 5 (IV) collagen trimersas the predominant collagen complex, a developmental changethat has been inferred to strengthen the GBM (Miner and Sanes,1994). Mutations in Alport syndrome disrupt the assembly of

3 4 5 (IV) collagen trimers, leading to the persistent promi-nence of 1 1 2 (IV) collagen complexes. As 3 4 5 (IV)collagen trimers represent half the total proteins of a mature


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body with multiple projections subdivided into larger majorprocesses and ner pedicels or FPs (Fig. 2, A and B). Majorprocesses are reinforced by microtubules and intermediate la-ments while FPs are actin-rich projections anchored to the GBM

via focal adhesions (Ichimura et al., 2003). The podocyte cellbodies and their FPs wrap around the glomerular capillaries in astrikingly elaborate interdigitating pattern. Neighboring podo-cytes are physically adjoined through their FPs via unique inter-cellular junctions called the SD (Fig. 3 B). Unlike tight junctions,the SD lacks E-cadherin and is structurally porous (Tassin et al.,1994). The SD thereby serves as the exit port for primary uri-nary ltrate and is now well recognized as essential in the selec-tive retention of high-molecular-weight plasma components.The seminal discoveries of the proteins nephrin and podocin asintegral components of the SD are instrumental in proving thatpodocytes and their structural integrity are of key importance inthe establishment and maintenance of the GFB (Kestil et al.,1998; Holzman et al., 1999; Ruotsalainen et al., 1999; Bouteet al., 2000; Schwarz et al., 2001; Huber et al., 2003). Inactivatingmutations of NPHS1 and NPHS2 , the respective genes encodingfor nephrin and podocin, lead to congenital nephropathy char-acterized by the collapse of FPs and the absence of SDs (Kestilet al., 1998; Boute et al., 2000). This stereotypical pathologicaltransformation of podocytes called effacement is a distinctivehallmark of podocyte injury and is strongly correlated with theonset of proteinuria.

Several genes, apart from NPHS1 and NPHS2 , that encodefor podocyte-specic proteins are strongly associated with the

type IV collagens, thereby inducing a pathological transforma-tion as observed in Alport disease. These imaging analyses bol-ster the argument that the ultrane pore structure of the GBMis key to normal ltration, and that proteinuria results from per-

turbing the molecular and structural organization of the GBM.The abundance of HSPGs such as agrin, perlecan, and col-lagen XVIII confers a net negative charge to the GBM, whichprompted a long-held assumption that the GBM is a critical de-terminant of the charge selectivity of the GFB (Rennke et al.,1975; Rennke and Venkatachalam, 1977; Harvey et al., 2007;van den Hoven et al., 2008; Goldberg et al., 2009). Geneticstudies in mice aimed at minimizing the net negative charge ofthe GBM have disputed this argument and failed to result inovert proteinuria (Rossi et al., 2003; Harvey et al., 2007; Chenet al., 2008; Goldberg et al., 2009; Hamano et al., 2010). Simi-larly, treatment of the GBM with heparanase in order to stripglycosaminoglycan-associated anionic charges did not cause

overt changes in glomerular morphology or induce proteinuria(van den Hoven et al., 2008). In light of these ndings it istempting to speculate that charge repulsion of circulating mac-romolecules in the GFB is primarily established within the glo-merular compartment instead of the GBM.

The nal gatekeepers: Renal podocytes

and their slit diaphragms (SDs)

The dening feature of normal fully differentiated podocytesis their elaborate cytoarchitecture, which resembles the stellatebody shape of an octopus, characterized by an arborized cell

Figure 3. Molecular organization of the GBMand the SD. (A) Highly stratied assembly ofGBM components. Laminin LM-521 and agrinare bimodally distributed, whereas collagenIV complexes are concentrated at the core ofthe GBM. The minor 1 1 2 collagen (Col) isnotably biased toward the glomerular endo-thelium. Both the predominant 3 4 5 and theless abundant 1 1 2 type IV collagens arenormally too distant from 1integrin recep-tor (IR) complexes on the podocyte side. Thissuggests that LM-521 and agrin but not type IVcollagens are the normal physiological ligandsof IR complexes expressed by podocytes.(B) Simplied representation of major adhesionreceptors (nephrin, Neph1, and Fat1) found inthe SD. Lipid-raft localization of the SD is de-pendent on the cholesterol-binding podocin. TheSD is coupled to both F-actin regulatory (NckN-WASPArp2/3 and CD2APArp2/3) and cellpolarity (Par6aPKC/ Cdc42) complexes.


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disease (Ebarasi et al., 2009, 2015; Slavotinek et al., 2015). Crbproteins are part of the CrbPatjPals1 polarity complex, whichworks alongside the Par3Par6aPKC / complex in directingthe apical localization of particular membrane-bound proteins.Crb2b suppression in zebrash leads to loss of polarized distri-bution of nephrin and the disruption of SD assembly (Ebarasiet al., 2009). In contrast, podocyte-specic ablation of Scribble,a determinant of basolateral trafcking, did not inhibit properSD formation (Hartleben et al., 2012). These studies suggestthat apical sorting predominates over basolateral sorting mech-anisms to specify the polarized and dynamic assembly of theSD complex.

Parallel bundles of actin laments and a network of corti-cal actin form the backbone of terminal FPs, and the pertur-bation of this cytoskeletal assembly is thought to underlie FPeffacement and the dismantling of the SD (Ichimura et al.,2003). Compound ablation of the adaptor molecules Nck1 andNck2 in podocytes causes proteinuria, which demonstrates thatthe SD is intimately and dynamically coupled to the actin cyto-skeleton (Jones et al., 2006). In vitro, oligomerized nephrin

interacts with Nck adaptors, leading to the recruitment of N-WASPand Arp2/3 complex that mediates localized polymerization ofactin laments (Jones et al., 2006; Verma et al., 2006). Nckadaptors are not only required during podocyte maturation butare also needed to maintain preformed FPs (Jones et al., 2009).Since Nck proteins also interact with the PINCHILKintegrincomplex, these adaptors could also help anchor podocytes tothe GBM via actin-linked focal contacts (Tu et al., 1999; Daiet al., 2006; El-Aouni et al., 2006). Similarly, the Rho GTPaseCdc42 is required to mediate the linkage between the actin cy-toskeleton and nephrin complexes (Scott et al., 2012). The cyto-skeletal tethering of the SD is also dependent on the scaffoldprotein CD2AP, which promotes the stability of actin microla-

ment network of podocytes (Shih et al., 1999; Kim et al., 2003;Yaddanapudi et al., 2011; Tang and Brieher, 2013).

Equally important to the assembly of the podocyte actincytoskeleton are opposing events counteracting actin lamentpolymerization. Slit1-Robo2 signaling antagonizes nephrin-dependent actin polymerization yet is required to establish a nor-mal pattern of FP interdigitation (Fan et al., 2012). Additionally,depletion of the actin-severing factor colin-1 has been shown tocause late-onset proteinuria and ultrastructural defects in podo-cytes in a manner akin to specic loss of Robo2 in podocytes(Ashworth et al., 2010; Garg et al., 2010). Mutations in ACTN4 (Kaplan et al., 2000), ARHGDIA (Togawa et al., 1999; Geeet al., 2013; Gupta et al., 2013), ARHGAP24 (Akilesh et al.,2011), INF2 (Brown et al., 2010), MYO1E (Krendel et al., 2009;Mele et al., 2011), and ANLN (Gbadegesin et al., 2014), whichencode for known regulators of the actin cytoskeleton, have allbeen implicated in the etiology of proteinuric diseases.

The cytoskeletal dynamics and structural plasticity of podo-cytes are also regulated by calcium signaling, lipidprotein inter-actions at the SD, and endocytosis. In podocytes, the ion channelsTrpc5 and Trpc6 mediate distinctive calcium inux in response toangiotensin II, eliciting the reorganization of the actin cytoskeletonvia modulation of the Rho GTPases Rac1 and RhoA (Tian et al.,2010). Gain-of-function mutations of TRPC6 are known to cause

onset of proteinuric diseases including CD2AP (Shih et al., 1999;Kim et al., 2003), Kirrel/Neph1 (Donoviel et al., 2001), Fat1 (Ciani et al., 2003), TRPC6 (Reiser et al., 2005; Winn et al., 2005),

ACTN4 (Kaplan et al., 2000), MYO1E (Krendel et al., 2009; Meleet al., 2011), ARHGAP24 (Akilesh et al., 2011), ARHGDIA (Togawa et al., 1999; Gee et al., 2013; Gupta et al., 2013), INF2 (Brown et al., 2010), COQ2 (Diomedi-Camassei et al., 2007),COQ6 (Heeringa et al., 2011), PLCE1 (Sadl et al., 2002; Hinkeset al., 2006), ANLN (Gbadegesin et al., 2014), PTPRO (Wharramet al., 2000; Ozaltin et al., 2011), and ADCK4 (Ashraf et al., 2013).Most of these genes encode for intrinsic SD components or theirrespective interacting partners while the rest encode for proteinsneeded for the survival, differentiation, cytoskeletal dynamics,and unique morphology of podocytes. The consequences of muta-tions of these genes highlight the important relationship betweenpodocyte dysfunction and the disruption of the GFB.

While many of the molecular constituents of the SDshave been identied, their topological assembly into a func-tional complex is poorly understood. The ectodomains of sev-eral adhesion receptors in the SD likely organize the bridge

linking juxtaposed FPs via a combination of homophilic andheterophilic receptorreceptor interactions. By virtue of theirlarge ectodomains, nephrin and Fat1 are excellent candidatesto associate in trans to connect opposing FPs (Inoue et al.,2001; Ciani et al., 2003; Khoshnoodi et al., 2003; Wartiovaaraet al., 2004). The smaller adhesion receptors such as Neph1and Neph3, however, may interact in cis with nephrin and Fat1(Gerke et al., 2003; Heikkil et al., 2011). Consistent with itsanatomical appearance as a junction between differentiatedpodocytes, other components of the SD are key moleculesassociated with adherens and tight junctions including ZO-1,CASK, spectrins, MAGI-2, JAMA-A, occludin, cingulin, andIQGAP1 (Lehtonen et al., 2005; Fukasawa et al., 2009). The

huge scaffold protein ZO-1 is essential for the normal interdig-itation of FPs and the formation of the SD (Itoh et al., 2014).Lack of ZO-1 triggers early onset proteinuria with podocyteeffacement and the progressive scarring of the glomerulus(glomerulosclerosis). ZO-1 appears to be required to maintainthe expression and correct spatial distribution of nephrin andpodocin. Consistently, ZO-1 expression is signicantly dimin-ished in models of diabetic nephropathy.

The distinctive morphology of podocytes underscores theimportance of cell polarity signaling in podocyte biology. TheSD marks the boundary between the apical and basolateralmembrane domains of podocytes. Nephrin and Neph1 are knownto interact with polarity proteins such as Par3, Par6, and aPKC / (Hartleben et al., 2008). The deletion of aPKC / and the smallGTPase Cdc42, which regulates the activation of the Par3-Par6-aPKC / polarity complex, causes proteinuria and the forma-tion of aberrant junctions between effaced FPs (Hirose et al.,2009; Huber et al., 2009; Scott et al., 2012; Blattner et al.,2013). Loss of aPKC / has been shown to interfere with cellsurface localization of nephrin, podocin, and Neph1 (Satohet al., 2014). Furthermore, studies in zebrash demonstrate thatthe Crumbs (Crb) protein family member Crb2b is required forthe differentiation of pronephric podocytes, whereas mutationsin the human orthologue CRB2 have been linked to proteinuric


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genes encoding for proteins implicated in the adhesion of podo-cytes to GBM components such as collagens and laminins, re-sults in impairment of the GFB. Intrinsic structural reorganizationof the GBM such as in Alport and Pierson syndrome may alsoperturb the normal anchorage of podocytes and endothelialcells, cumulatively altering the compressibility of the GBM.This is not at all far-fetched, as ECM stiffness, by way of mech-anotransduction via adhesion molecules, is known to inuencea diverse range of cellular behavior including restructuring ofthe actin cytoskeleton, contractility, motility, gene expression,proliferation, and overall differentiation (DuFort et al., 2011).

Effaced podocyte FPs could very well be indicative of not just the remodeling of cellcell junctions or SDs but also of amaladaptive response to reestablish weakening focal contactson the GBM. In fact, unfastening of podocytes and denudedGBM are common in the progression of diabetic nephropathyand chronic kidney disease (Toyoda et al., 2007; Weil et al.,2012; Kriz and Lemley, 2015), whereas endothelial detachmenthas been observed in Vegfa -null mutant mice (Eremina et al.,2003). Interestingly, comparison of the elastic properties of pu-

ried glomeruli by atomic force microscopy reveals that glo-merular rigidity is reduced by as much as 30% in mouse modelsof Alport syndrome ( Col4a3 knockout) and HIV-induced ne-phropathy (HIVAN) before the onset of overt pathological his-tology (Wyss et al., 2011). Increased glomerular deformabilitycorrelating with increased permeability of the GFB is likelysymptomatic of an aberrant interaction between the GBM andthe cells attached to it.

Streaming potential and charge selectivity

in renal ltration

An attractive hypothesis based on electrokinetic principles hasbeen proposed to account for the charge selectivity in renal l-

tration. Micropuncture measurements on salamander ( Necturusmaculosus ) glomeruli demonstrate that ltration pressure estab-lishes a distinctive streaming potential or charge differenceacross the GFB, with the Bowmans space being more negativethan the endothelial lumen (Fig. 4, A and B; Hausmann et al.,2010). The phenomenon of streaming potentials arises whenelectrolytes are forced by a pressure gradient across porousmedia or a channel carrying a permanent charge. In essence, theelectrokinetic model posits that when small cations traverse theGFB, they bind and counterbalance the negatively charged sur-faces within the GFB, reaching a threshold at which net ionicmovement of small cations lags behind that of small anions(Hausmann et al., 2012; Moeller and Tenten, 2013). This differ-ential advance of oppositely charged small ions thereby estab-lishes a net charge separation and a measurable electrical eldthat polarizes the GFB. The streaming potential hypothesistherefore predicts that larger anions such as native albuminwould encounter a retrograde electrophoretic eld running op-posite to the direction of hydraulic ux (Fig. 4 C). Given theminor importance of negative charges within the GBM, it canbe inferred that the streaming potential is largely initiated fromthe highly charged ESL. The nding that neutral albumin tra-verses the GFB independent of the glomerular ltration ratewhereas native anionic albumin passage becomes increasingly

proteinuria in humans, whereas genetic loss of Trpc5 or Trpc6 prevents podocyte injury (Reiser et al., 2005; Winn et al., 2005;Schaldecker et al., 2013). These ndings suggest that unbal-anced elevation of intracellular calcium mitigates podocyte dys-function and provide an explanation as to the protective benetsof blockade of angiotensin signaling in the progression of pro-teinuric renal diseases such as glomerulosclerosis and diabeticnephropathy. Interestingly, Trpc6 interacts with podocin, whichsuggests how intimately calcium signaling is coupled to the SDcomplex (Huber et al., 2007; Schurek et al., 2014). Lipid-dependent autocrine signaling in podocytes involving sFlt1 isrequired in the regulation of actin dynamics and the properformation of FPs and the SDs (Jin et al., 2012). Specically,sFlt1 secreted by podocytes binds to the glycosphingolipid GM3at the podocyte surface, promoting cell adhesion, nephrinphosphorylation, and consequent remodeling of the cytoskele-ton. Defective endocytosis in podocytes has also been shown toimpair renal ltration. FP effacement and proteinuria ensues inthe absence of endocytosis-related lipid-binding proteins, spe-cically dynamins, endophilins, and synaptojanin-1 (Soda et al.,

2012). It has been postulated that clathrin-mediated endocytosiscould dynamically sculpt FPs by regulating the turnover of SDcomponents (Soda and Ishibe, 2013).

Podocytes also play multiple important functions in main-taining the GFB independent of the formation of the SDs. Podo-cytes have a vital role in promoting the proliferation, survival, anddevelopment of endothelial cells. The pro-angiogenic factorsVEGFA, Angpt1, and SDF1 are secreted by podocytes and are es-sential for the normal development of the glomerular endothelium(Simon et al., 1998; Yuan et al., 1999; Satchell et al., 2002;Takabatake et al., 2009; Haege et al., 2012). Podocytes togetherwith the glomerular endothelium also collaborate in building theGBM (Byron et al., 2014). Whereas 1 1 2 (IV) collagen is pro-

duced jointly by endothelial cells and podocytes, the 3 4 5 (IV)collagen network is derived primarily from podocytes, as seenin vivo (Abrahamson et al., 2009). Macromolecules and pro-teins that traverse the GBM can be sequestered by podocytes viaendocytosis, a mechanism that likely prevents the GFB from clog-ging (Eyre et al., 2007; Akilesh et al., 2008). Megalin and cubilin,which form a multifunctional endocytic receptor complex com-monly found in absorptive epithelia, are coexpressed in podocytesand could mediate the retrieval of urinary albumin by podocytes(Yamazaki et al., 2004; Prabakaran et al., 2012). Overwhelminggenetic evidence undeniably underscores the fact that the podo-cyte is an essential component of the GFB.

The importance of cell adhesion to the GBM

Biophysical studies demonstrate that GBM compression re-duces permeability to albumin and the polysaccharide Ficoll(Robinson and Walton, 1989; Fissell et al., 2009). It is thereforetempting to speculate based on this that GECs and podocytesphysically constrain and mitigate compression of the GBM.Consistent with this supposition are genetic studies showingthat loss of Itga3 (Kreidberg et al., 1996), Itgb1 (Pozzi et al.,2008), Cd151 (Karamatic Crew et al., 2004; Sachs et al., 2006),

Ddr1 (Gross et al., 2004), Ilk (Dai et al., 2006; El-Aouni et al.,2006), Tln1 (Tian et al., 2014), and Rap1a/b (Potla et al., 2014),


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an emerging theme that the GFB, despite being multilayered,consists of components with dynamically intertwined roles, no

single one of which is more important than the others, that har-monize together into one functionally elegant ensemble. Con-tinued efforts to rene our understanding of the mechanism ofrenal ltration and the biology of the GFB are invaluable forthe development of better therapeutic strategies to alleviate theburden of proteinuric diseases.

This work was funded by the National Institutes of Health (grant R01HL12412The authors declare no competing nancial interests.

Submitted: 6 October 2014 Accepted: 7 April 2015

References

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more restricted with increasing glomerular pressure is congru-ent with an electrokinetic model of the GFB (Lund et al., 2003).

Similarly, albumin readily diffuses and equilibrates across theGFB once plasma ow is halted (Ryan and Karnovsky, 1976).

The hypothesis also predicts that podocyte FP effacementcan be detrimental to the generation of a streaming potential asmore rapidly advancing small anions bounce back upon encoun-tering the broadened FPs, causing the electrical eld across theGFB to be short-circuited (Hausmann et al., 2010, 2012). Hence,normal podocytes with their elaborate and regular network of FPsand SDs guarantees that streaming potential and ltration occuruniformly across the GFB. Further proof regarding this predic-tion is needed and should ideally be based on recording glo-merular streaming potentials in the context of proteinuric diseasemodels in mice. Nevertheless, in salamander glomeruli, stream-ing potentials are reversibly blocked by protamine, a polycationicprotein that neutralizes the negative charge of the GFB and iswell-known to induce proteinuria (Hausmann et al., 2010).

Conclusions

The robustness of the GFB depends on the plasticity and thedynamic signaling between its distinctive layers. Vigorous in-vestigations on this subject over the years have shown that tar-geted damage to any one layer can lead to collapse of the GFB,and that in many cases compromising one layer has inevitabledeleterious repercussions for the other layers. These highlight

Figure 4. Electrokinetic model of renal ltration. (A) Experimental setup used to demonstrate the existence of a ow-dependent electrical potential (stream-ing potential) across the GFB in salamander (N. maculosus ) glomeruli (Hausmann et al., 2010). P, potential electrode; R, reference electrode. Small ions,due to differential interaction with the negatively charged GFB, create a net gradient of charges measurable as a streaming potential (blue arrows), makingthe endothelial lumen (EL) more positive than the Bowmans space (BS). (B) Filtration pressure dependence of glomerular streaming potential. (C) Retrograelectrophoretic eld created by streaming potentials. Due to streaming potentials, macromolecules encounter a dynamic electrophoretic eld (green arrow)that is opposite to that of diffusive and convective uxes (purple arrow). Albumin, a negatively charged macromolecule, would not only encounter sizedependent exclusion by the GFB but would effectively be electrophoresed away from the GFB during the course of act ive ltration.

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Tian, X., J.J. Kim, S.M. Monkley, N. Gotoh, R. Nandez, K. Soda, K. Inoue,D.M. Balkin, H. Hassan, S.H. Son, et al. 2014. Podocyte-asso

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